The field of single-cell genomics provides new perspectives to the understanding of genetics by bringing the study of genomes to the cellular level, and opens up new frontiers by dissecting the contributions of individual cells to the biology of ecosystems and organisms. For example, it is now possible to use single-cell genomics to identify and assemble the genomes of unculturable microorganisms (Marcy et al.), evaluate the roles of genetic mosaicism in normal physiology and disease (McConnell et al.), and determine the contributions of intra-tumor genetic heterogeneity in cancer development or treatment response (Wang et al.).
However, this field relies on the study of nucleic acid of very low quantity, such as genomic DNA from a single cell, which requires amplification of the low quantity nucleic acid. Current amplification methods include thermostable DNA polymerase mediated PCR (Troutt et al., Telenius et al.), isothermal DNA polymerase mediated multiple displacement amplification or MDA (Dean et al., Zhang et al. 2001), and hybrid methods such as PicoPLEX (Langmore) and MALBAC (Zong et al.). These methods frequently cause loss of signal from the low quantity of DNA during the amplification due to differences in PCR priming efficiency among sequences, and/or introduction of errors by thermostable polymerases. The errors and biases introduced during these methods, cause problems such as loss of coverage, decreased coverage uniformity, allelic imbalance, allelic dropout, and errors affecting detection of single nucleotide variation and measurement of copy number variation especially during single cell genome or exome amplification. See de Bourcy et al., Gawad et al., Hou et al., Huang et al.